Laboratory for Anti-Geric Testing, Evaluation and Research Funding is sought for a series of investigations of interventions thought likely to extend life span in a population of genetically heterogeneous mice. The protocol will test five new interventions each year in Phase I screening studies, as well as conducting more comprehensive Phase II studies for selected interventions in Years 3, 4, and 5. Key features of the Phase I protocol include: (a) use of asymmetric group assignment to maximize statistical power by over sampling control animals; (b) use of separate monitor mice to document drug distribution and effectiveness; and (c) complete assessment of life table for all Phase I interventions. Phase I studies will include assessments of several age-sensitive traits as indirect indices of biological age, including (a) spontaneous activity; (b) IGF-I, glucocorticoid, and glycated hemoglobin levels, (c) five T cell subsets; (d) cataract severity; and (e) tests of learning and memory. Limited necropsy analyses will be done on all Phase I mice, and comprehensive necropsy analysis will be available for all Phase II mice and for those Phase I mice exposed to interventions found either to increase or to decrease longevity to a significant extent. Phase II studies will, in addition to replication of tests used in Phase I, add more comprehensive examinations of immune function, liver enzyme heat stability, eye lens protein extraction rates, tail tendon break time, and array-based analysis of age-sensitive liver and muscle mRNAs. Four interventions are suggested for initial exploration: (a) piaglitazone, an enhancer of insulin sensitivity, (b) pyridoxamine, which inhibits glycation-based cross links, (c) a-phenyl-N-tert-butyl nitrone (PBN), a scavenger of free radicals, and (d) pegvisomant, an inhibitor of GH action. The project as a whole should serve two important functions: providing critical tests of hypotheses that specific varieties of intervention will delay aging or late life illnesses in mammals; and, perhaps more importantly, provide important new leads to biochemical or hormonal pathways that can indeed modulate aging and delay late life illnesses and disabilities.